Common and distinct features of mammary tumors driven by Pten-deletion or activating Pik3ca mutation

Abstract

PTEN loss and PIK3CA activation both promote the accumulation of phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3). While these proteins also have distinct biochemical functions, beyond the regulation of PIP3, little is known about the consequences of these differences in vivo. Here, we directly compared cancer signalling in mammary tumors from MMTV-Cre:Ptenf/f and MMTV-Cre:Pik3caLSL-H1047R mice. Using unsupervised hierarchical clustering we found that whereas MMTV-Cre:Pik3caLSL-H1047R-derived tumors fall into two separate groups, designated squamous-likeEx and class14Ex, MMTV-Cre:Ptenf/f tumors cluster as one group together with PIK3CAH1047R class14Ex, exhibiting a ‘luminal’ expression profile. Gene Set Enrichment Analysis (GSEA) of Pten∆ and PIK3CAH1047R class14Ex tumors revealed very similar profiles of signalling pathways as well as some interesting differences. Analysis of 18 signalling signatures revealed that PI3K signalling is significantly induced whereas EGFR signalling is significantly reduced in Pten∆ versus PIK3CAH1047R tumors. Thus, Pten∆ and PIK3CAH1047R tumors exhibit discernable differences that may impact tumorigenesis and response to therapy.